LORBRENA (lorlatinib) 10 Clinical Pharmacology

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10.1 Mechanism of Action

Lorlatinib is a selective, adenosine triphosphate (ATP) competitive, brain-penetrant, small molecule inhibitor of ALK and ROS1 tyrosine kinases that addresses mechanisms of resistance following previous treatment with ALK inhibitor therapy.

10.2 Pharmacodynamics

In nonclinical studies, lorlatinib potently inhibited catalytic activities of non‑mutated ALK and a broad range of clinically relevant ALK mutant kinases in recombinant enzyme and cell-based assays. The ALK mutations analyzed included those conferring resistance to other ALK inhibitors.

Lorlatinib demonstrated marked antitumor activity at low nanomolar free plasma concentrations in mice bearing tumor xenografts that express echinoderm microtubule‑associated protein‑like 4 (EML4) fusions with ALK variant 1 (v1), including ALK mutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T, are known to confer resistance to first and second generation ALK inhibitors. Lorlatinib is also capable of penetrating the blood‑brain barrier and achieved efficacious brain exposure in mice and rat. In mice bearing orthotropic EML4‑ALK or EML4‑ALKL1196M brain tumor implants, lorlatinib caused tumor shrinkage and prolonged survival. The overall antitumor efficacy of lorlatinib was dose-dependent and correlated with inhibition of ALK phosphorylation.

Cardiac electrophysiology

QT interval

In B7461001, 2 patients (0.7%) had absolute Fridericia’s correction QTc (QTcF) values >500 msec, and 5 patients (1.8%) had a change in QTcF from baseline >60 msec.

In addition, the effect of a single oral dose of lorlatinib (50 mg, 75 mg, and 100 mg) with and without 200 mg once daily itraconazole was evaluated in a 2-way crossover study in 16 healthy volunteers. No increases in the mean QTc interval were observed at the mean observed lorlatinib concentrations in this study.

PR interval

In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (90% CI: 13.4, 19.4 ms). Among the 284 patients with PR interval <200 ms, 14% (40 patients) had PR interval prolongation ≥200 ms after starting lorlatinib. The prolongation of PR interval occurred in a concentration dependent manner. Atrioventricular block occurred in 1.0% of patients.
For those patients who develop PR prolongation, dose modification may be required (see 4 DOSAGE AND ADMINISTRATION).

10.3 Pharmacokinetics


In patients with cancer, peak lorlatinib concentrations in plasma are rapidly reached with the median Tmax of 1.2hours following a single 100 mg dose and 2.0 hours following 100 mg once daily multiple dosing.

After oral administration of lorlatinib tablets, the mean absolute bioavailability is 80.8% (90% CI: 75.7%, 86.2%) compared to intravenous administration.

Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher AUCinf and 9% lower Cmax (AUCinf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%; Cmax ratio of 90.89%; 90% CI for the ratio: 84.82%, 97.40%), compared to overnight fasting. Lorlatinib may be administered with or without food. The proton pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (AUCinf ratio of 100.9%; 90% CI for the ratio: 97.6%, 104.3%). No dose adjustment is recommended when lorlatinib is taken with proton pump inhibitors, H2 receptor antagonists or locally acting antacids.

After multiple QD dose administration, lorlatinib Cmax increased dose-proportionally and AUCtau increased slightly less than dose-proportionally over the dose range of 10 mg to 200 mg QD.

At the 100 mg once daily lorlatinib dose, the Cycle 1 Day 15 geometric mean (geometric %CV) peak plasma concentration was 577 (42 ng/mL and the AUC24 5650 (39) ng·h/mL in patients with cancer. The geometric mean (geometric %CV) oral clearance was 17.7 (39) L/h.


In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to both albumin and α1-acid glycoprotein.

The geometric mean (geometric %CV) steady state volume of distribution (Vss) of lorlatinib was 305 (28) L following 50 mg IV administration to healthy subjects. In patients with cancer, the geometric mean (geometric %CV) Vz/F after 100 mg single dose was 352 (37) L.


In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways. In vitro data indicate that lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

In plasma, a benzoic acid metabolite of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib was observed as a major metabolite, accounting for 21% of the circulating radioactivity. The oxidative cleavage metabolite is pharmacologically inactive.


In patients with cancer, the plasma half life of lorlatinib after a single 100 mg dose was 23.6 hours. At steady state, lorlatinib plasma exposures are lower than those expected from single dose pharmacokinetics, indicating a net auto induction effect on lorlatinib metabolism. Following oral administration of a 100 mg radiolabeled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in feces, with overall mean total recovery of 88.6%.

Unchanged lorlatinib was the major component of human plasma and feces, accounting for 44% and 9.1% of total radioactivity in plasma and feces, respectively. Less than 1% of unchanged lorlatinib was detected in urine.

Special Populations and Conditions

  • Pediatrics The safety and efficacy of LORBRENA (lorlatinib) in pediatric patients have not been established.
  • Geriatrics Out of the 476 patients who received lorlatinib 100 mg orally once daily in B7461001 (N=327) and Study B7461006 (N=149), 25.5% of patients were aged 65 years or older. Of the 215 patients in the efficacy population in Study B7461001, 17.7% of patients were aged 65 years or older, and of the 149 patients in the lorlatinib arm of Study B7461006, 40% were aged 65 years or older. No clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years of age and younger patients (see 4 DOSAGE AND ADMINISTRATION).
  • Age, gender, race, body weight, and phenotype: Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight, or phenotypes for CYP3A5 and CYP2C19.
  • Hepatic Insufficiency As lorlatinib is metabolized in the liver, hepatic impairment is likely to increase lorlatinib plasma concentrations. Clinical studies that were conducted excluded patients with AST or ALT >2.5 × ULN, or if due to underlying malignancy, >5.0 × ULN or with total bilirubin >1.5 × ULN. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild hepatic impairment (n=50). No dose adjustments are recommended for patients with mild hepatic impairment (see 4 DOSAGE AND ADMINISTRATION). LORBRENA has not been studied in patients with moderate or severe hepatic impairment.
  • Renal Insufficiency Less than 1% of the administered dose is detected unchanged lorlatinib in urine. Clinical studies excluded patients with serum creatinine >1.5 × ULN or estimated CLcr <60 mL/min. Population pharmacokinetic analyses have shown that lorlatinib steady state exposure was not clinically meaningfully altered in patients with mild (n=103, CL cr: 60-89 mL/min) or moderate renal impairment (n=41, CL cr: 30-59 mL/min). Based on a renal impairment study, no dose adjustments are recommended for patients with mild or moderate renal impairment [absolute eGFR based on Modification of Diet in Renal Disease Study equation (MDRD)-derived eGFR (in mL/min/1.73 m2) × measured body surface area/1.73 ≥30 mL/min]. In this study, lorlatinib AUCinf increased by 41% in subjects with severe renal impairment (absolute eGFR<30 mL/min) compared to subjects with normal renal function (absolute eGFR≥90 mL/min). -Reduce the recommended dosage of LORBRENA in patients with severe renal impairment, from 100 mg to 75 mg orally once daily (see 4 DOSAGE AND ADMINISTRATION).